Electromagnetic treatment apparatus and method for angiogensis modulation of living tissues and cells

ABSTRACT

An apparatus and method for electromagnetic treatment of living tissues and cells comprising: configuring at least one waveform according to a mathematical model having at least one waveform parameter, said at least one waveform to be coupled to a angiogenesis and neovascularization target pathway structure; choosing a value of said at least one waveform parameter so that said at least waveform is configured to be detectable in said angiogenesis and neovascularization target pathway structure above background activity in said target pathway structure; generating an electromagnetic signal from said configured at least one waveform; and coupling said electromagnetic signal to said angiogenesis and neovascularization target pathway structure using a coupling device.

This application claims the benefit of U.S. Provisional Application60/563,104 filed Apr. 19, 2004.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention pertains generally to an apparatus and a method fortreatment of living tissues and cells by altering their interaction withtheir electromagnetic environment. This invention also relates to amethod of modification of cellular and tissue growth, repair,maintenance, and general behavior by application of encodedelectromagnetic information. More particularly this invention relates tothe application of surgically non-invasive coupling of highly specificelectromagnetic signal patterns to any number of body parts. Inparticular, an embodiment according to the present invention pertains tousing pulsing electromagnetic fields (“PEMF”) to enhance living tissuegrowth and repair via angiogenesis and neovascularization by affectingthe precursors to growth factors and other cytokines, such as ion/ligandbinding such as calcium binding to calmodoulin.

2. Discussion of Related Art

It is now well established that application of weak non-thermalelectromagnetic fields (“EMF”) can result in physiologically meaningfulin vivo and in vitro bioeffects.

EMF has been used in applications of bone repair and bone healing.Waveforms comprising low frequency components and low power arecurrently used in orthopedic clinics. Origins of using bone repairsignals began by considering that an electrical pathway may constitute ameans through which bone can adaptively respond to EMF signals. A linearphysicochemical approach employing an electrochemical model of a cellmembrane predicted a range of EMF waveform patterns for which bioeffectsmight be expected. Since a cell membrane was a likely EMF target, itbecame necessary to find a range of waveform parameters for which aninduced electric field could couple electrochemically at the cellularsurface, such as voltage-dependent kinetics. Extension of this linearmodel also involved Lorentz force analysis.

A pulsed radio frequency (“PRE”) signal derived from a 27.12 MHzcontinuous sine wave used for deep tissue healing is known in the priorart of diathermy. A pulsed successor of the diathermy signal wasoriginally reported as an electromagnetic field capable of eliciting anon-thermal biological effect in the treatment of infections. PRFtherapeutic applications have been reported for reduction ofpost-traumatic and post-operative pain and edema in soft tissues, woundhealing, burn treatment and nerve regeneration. Application of EMF forthe resolution of traumatic edema has become increasingly used in recentyears. Results to date using PRF in animal and clinical studies suggestthat edema may be measurably reduced from such electromagnetic stimulus.

Prior art considerations of EMF dosimetry have not taken into accountdielectric properties off tissue structure as opposed to the propertiesof isolated cells.

In recent years, clinical use of non-invasive PRF at radio frequenciescomprised using pulsed bursts of a 27.12 MHz sinusoidal wave, whereineach pulse burst comprises a width of sixty-five microseconds, havingapproximately 1,700 sinusoidal cycles per burst, and various burstrepetition rates. By use of a substantially single voltage amplitudeenvelope with each PRF burst, one was limiting frequency components thatcould couple to relevant dielectric pathways in cells and tissue.

Time-varying electromagnetic fields, comprising rectangular waveformssuch as pulsing electromagnetic fields, and sinusoidal waveforms such aspulsed radio frequency fields ranging from several Hertz to an about 15to an about 40 MHz range, are clinically beneficial when used as anadjunctive therapy for a variety of musculoskeletal injuries andconditions.

Beginning in the 1960's, development of modern therapeutic andprophylactic devices was stimulated by clinical problems associated withnon-union and delayed union bone fractures. Early work showed that anelectrical pathway can be a means through which bone adaptively respondsto mechanical input. Early therapeutic devices used implanted andsemi-invasive electrodes delivering direct current (“DC”) to a fracturesite. Non-invasive technologies were subsequently developed usingelectrical and electromagnetic fields. These modalities were originallycreated to provide a non-invasive “no-touch” means of inducing anelectrical/mechanical waveform at a cell/tissue level. Clinicalapplications of these technologies in orthopaedics have led to approvedapplications by regulatory bodies worldwide for treatment of fracturessuch as non-unions and fresh fracture, as well as spine fusion.Presently several EMF devices constitute the standard armamentarium oforthopaedic clinical practice for treatment of difficult to healfractures. The success rate for these devices has been very high. Thedatabase for this indication is large enough to enable its recommendeduse as a safe, non-surgical, non-invasive alternative to a first bonegraft. Additional clinical indications for these technologies have beenreported in double blind studies for treatment of avascular necrosis,tendinitis, osteoarthritis, wound repair, blood circulation and painfrom arthritis as well as other musculoskeletal injuries.

Cellular studies have addressed effects of weak low frequencyelectromagnetic fields, on both signal transduction pathways and growthfactor synthesis. It can be shown that EMF stimulates secretion ofgrowth factors after a short, trigger-like duration. Ion/ligand bindingprocesses at a cell membrane are generally considered an initial EMFtarget pathway structure. The clinical relevance to treatments forexample of bone repair, is upregulation such as modulation, of growthfactor production as part of normal molecular regulation of bone repair.Cellular level studies have shown effects on calcium ion transport, cellproliferation, Insulin Growth Factor (“IGF-II”) release, and IGF-IIreceptor expression in osteoblasts. Effects on Insulin Growth Factor-I(“IGF-I”) and IGF-II have also been demonstrated in rat fracture callus.Stimulation of transforming growth factor beta (“TGF-β”) messenger RNA(“mRNA”) with PEMF in a bone induction model in a rat has been shown.Studies have also demonstrated upregulation of TGF-β mRNA by PEMF inhuman osteoblast-like cell line designated MG-63, wherein there wereincreases in TGF-β1, collagen, and osteocalcin synthesis. PEMFstimulated an increase in TGF-β1 in both hypertrophic and atrophic cellsfrom human non-union tissue. Further studies demonstrated an increase inboth TGF-β1 mRNA and protein in osteoblast cultures resulting from adirect effect of EMF on a calcium/calmodulin-dependent pathway.Cartilage cell studies have shown similar increases in TGF-β1 mRNA andprotein synthesis from EMF, demonstrating a therapeutic application tojoint repair. Various studies conclude that upregulation of growthfactor production may be a common denominator in the tissue levelmechanisms underlying electromagnetic stimulation. When using specificinhibitors, EMF can act through a calmodulin-dependent pathway. It hasbeen previously reported that specific PEMF and PRF signals, as well asweak static magnetic fields, modulate Ca²⁺ binding to CaM in a cell-freeenzyme preparation. Additionally, upregulation of mRNA for BMP2 and BMP4with PEMF in osteoblast cultures and upregulation of TGF-β1 in bone andcartilage with PEMF have been demonstrated.

However, prior art in this field does not configure waveforms based upona ion/ligand binding transduction pathway. Prior art waveforms areinefficient since prior art waveforms apply unnecessarily high amplitudeand power to living tissues and cells, require unnecessarily longtreatment time, and cannot be generated by a portable device.

Therefore, a need exists for an apparatus and a method that moreeffectively modulate angiogenesis and other biochemical processes thatregulate tissue growth and repair, shortens treatment times, andincorporates miniaturized circuitry and light weight applicators thusallowing the apparatus to be portable and if desired disposable. Afurther need exists for an apparatus and method that more effectivelymodulates angiogenesis and other biochemical processes that regulatetissue growth and repair, shortens treatment times, and incorporatesminiaturized circuitry and light weight applicators that can beconstructed to be implantable.

SUMMARY OF THE INVENTION

An apparatus an a method for electromagnetic treatment of living tissuesand cells by altering their interaction with their electromagneticenvironment.

According to an embodiment of the present invention, by treating aselectable body region with a flux path comprising a succession of EMFpulses having a minimum width characteristic of at least about 0.01microseconds in a pulse burst envelope having between about 1 and about100,000 pulses per burst, in which a voltage amplitude envelope of saidpulse burst is defined by a randomly varying parameter in whichinstantaneous minimum amplitude thereof is not smaller than the maximumamplitude thereof by a factor of one tenth-thousandth. The pulse burstrepetition rate can vary from about 0.01 to about 10,000 Hz. Amathematically definable parameter can also be employed to define anamplitude envelope of said pulse bursts.

By increasing a range of frequency components transmitted to relevantcellular pathways, access to a large range of biophysical phenomenaapplicable to known healing mechanisms, including enhanced enzymeactivity and growth factor and cytokine release, is advantageouslyachieved.

According to an embodiment of the present invention, by applying arandom, or other high spectral density envelope, to a pulse burstenvelope of mono- or bi-polar rectangular or sinusoidal pulses whichinduce peak electric fields between 10⁻⁶ and 10 volts per centimeter(V/cm), a more efficient and greater effect can be achieved onbiological healing processes applicable to both soft and hard tissues inhumans, animals and plants. A pulse burst envelope of higher spectraldensity can advantageously and efficiently couple to physiologicallyrelevant dielectric pathways, such as, cellular membrane receptors, ionbinding to cellular enzymes, and general transmembrane potential changesthereby modulating angiogenesis and neovascularization.

By advantageously applying a high spectral density voltage envelope as amodulating or pulse-burst defining parameter, power requirements forsuch modulated pulse bursts can be significantly lower than that of anunmodulated pulse. This is due to more efficient matching of thefrequency components to the relevant cellular/molecular process.Accordingly, the dual advantages of enhanced transmitting dosimetry torelevant dielectric pathways and of decreasing power requirements areachieved.

A preferred embodiment according to the present invention utilizes aPower Signal to Noise Ratio (“Power SNR”) approach to configurebioeffective waveforms and incorporates miniaturized circuitry andlightweight flexible coils. This advantageously allows a device thatutilizes a Power SNR approach, miniaturized circuitry, and lightweightflexible coils, to be completely portable and if desired to beconstructed as disposable and if further desired to be constructed asimplantable.

Specifically, broad spectral density bursts of electromagneticwaveforms, configured to achieve maximum signal power within a bandpassof a biological target, are selectively applied to target pathwaystructures such as living organs, tissues, cells and molecules.Waveforms are selected using a unique amplitude/power comparison withthat of thermal noise in a target pathway structure. Signals comprisebursts of at least one of sinusoidal, rectangular, chaotic and randomwave shapes, have frequency content in a range of about 0.01 Hz to about100 MHz at about 1 to about 100,000 bursts per second, and have a burstrepetition rate from about 0.01 to about 1000 bursts/second. Peak signalamplitude at a target pathway structure such as tissue, lies in a rangeof about 1 μV/cm to about 100 mV/cm. Each signal burst envelope may be arandom function providing a means to accommodate differentelectromagnetic characteristics of healing tissue. A preferredembodiment according to the present invention comprises about 0.1 toabout 100 millisecond pulse burst comprising about 1 to about 200microsecond symmetrical or asymmetrical pulses repeating at about 0.1 toabout 100 kilohertz within the burst. The burst envelope is a modified1/f function and is applied at random repetition rates between about 0.1and about 1000 Hz. Fixed repetition rates can also be used between about0.1 Hz and about 1000 Hz. An induced electric field from about 0.001mV/cm to about 100 mV/cm is generated. Another embodiment according tothe present invention comprises an about 0.01 millisecond to an about 10millisecond burst of high frequency sinusoidal waves, such as 27.12 MHz,repeating at about 1 to about 100 bursts per second. An induced electricfield from about 0.001 mV/cm to about 100 mV/cm is generated. Resultingwaveforms can be delivered via inductive or capacitive coupling.

It is an object of the present invention to provide modulation ofelectromagnetically sensitive regulatory processes at the cell membraneand at junctional interfaces between cells.

It is another object of the present invention to provide anelectromagnetic method of treatment of living cells and tissuescomprising a broad-band, high spectral density electromagnetic field.

It is a further object of the present invention to provide anelectromagnetic method of treatment of living cells and tissuescomprising amplitude modulation of a pulse burst envelope of anelectromagnetic signal that will induce coupling with a maximum numberof relevant EMF-sensitive pathways in cells or tissues.

It is another object of the present invention to provide increased bloodflow to affected tissues by modulating angiogenesis andneovascularization.

It is another object of the present invention to provide increased bloodflow to enhance viability, growth, and differentiation of implantedcells, such as stem cells, tissues and organs.

It is another object of the present invention to provide increased bloodflow in cardiovascular diseases by modulating angiogenesis andneovascularization.

It is another object of the present invention to improve micro-vascularblood perfusion and reduced transudation.

It is a another object of the present invention to provide a treatmentof maladies of the bone and other hard tissue by modulating angiogenesisand neovascularization.

It is a still further object of the present invention to provide atreatment of edema and swelling of soft tissue by increased blood flowthrough modulation of angiogenesis and neovascularization.

It is another object of the present invention to provide anelectromagnetic method of treatment of living cells and tissues that canbe used for repair of damaged soft tissue.

It is yet another object of the present invention to increase blood flowto damaged tissue by modulation of vasodilation and stimulatingneovascularization.

It is a yet further object of the present invention to provide anapparatus for modulation of angiogenesis and neovascularization that canbe operated at reduced power levels and still possess benefits ofsafety, economics, portability, and reduced electromagneticinterference.

It is an object of the present invention to configure a power spectrumof a waveform by mathematical simulation by using signal to noise ratio(“SNR”) analysis to configure a waveform optimized to modulateangiogenesis and neovascularization then coupling the configuredwaveform using a generating device such as ultra lightweight wire coilsthat are powered by a waveform configuration device such as miniaturizedelectronic circuitry.

It is another object of the present invention to modulate angiogenesisand neovascularization by evaluating Power SNR for any target pathwaystructure such as molecules, cells, tissues and organs of plants,animals and humans using any input waveform, even if electricalequivalents are non-linear as in a Hodgkin-Huxley membrane model.

It is another object of the present invention to provide a method andapparatus for treating plants, animals and humans using electromagneticfields, selected by optimizing a power spectrum of a waveform to beapplied to a biochemical target pathway structure to enable modulationof angiogenesis and neovascularization within molecules, cells, tissuesand organs of a plant, animal, and human.

It is another object of the present invention to significantly lowerpeak amplitudes and shorter pulse duration. This can be accomplished bymatching via Power SNR, a frequency range in a signal to frequencyresponse and sensitivity of a target pathway structure such as amolecule, cell, tissue, and organ, of plants, animals and humans toenable modulation of angiogenesis and neovascularization.

The above and yet other objects and advantages of the present inventionwill become apparent from the hereinafter set forth Brief Description ofthe Drawings, Detailed Description of the Invention, and Claims appendedherewith.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the present invention will be described belowin more detail, with reference to the accompanying drawings:

FIG. 1 is a flow diagram of a electromagnetic treatment method forangiogenesis modulation of living tissues and cells according to anembodiment of the present invention;

FIG. 2 is a view of control circuitry according to a preferredembodiment of the present invention;

FIG. 3 is a block diagram of miniaturized circuitry according to apreferred embodiment of the present invention;

FIG. 4 depicts a waveform delivered to a angiogenesis andneovascularization target pathway structure according to a preferredembodiment of the present invention.

DETAILED DESCRIPTION

Induced time-varying currents from PEMF or PRF devices flow in a targetpathway structure such as a molecule, cell, tissue, and organ, and it isthese currents that are a stimulus to which cells and tissues can reactin a physiologically meaningful manner. The electrical properties of atarget pathway structure affect levels and distributions of inducedcurrent. Molecules, cells, tissue, and organs are all in an inducedcurrent pathway such as cells in a gap junction contact. Ion or ligandinteractions at binding sites on macromolecules that may reside on amembrane surface area voltage dependent processes, that iselectrochemical, that can respond to an induced electromagnetic field(“E”). Induced current arrives at these sites via a surrounding ionicmedium. The presence of cells in a current pathway causes an inducedcurrent (“J”) to decay more rapidly with time (“J(t)”). This is due toan added electrical impedance of cells from membrane capacitance andtime constants of binding and other voltage sensitive membrane processessuch as membrane transport.

Equivalent electrical circuit models representing various membrane andcharged interface configurations, have been derived. For example, inCalcium (“Ca²⁺”) binding, the change in concentration of bound Ca²⁺ at abinding site due to induced E may be described in a frequency domain byan impedance expression such as:${Z_{b}(\omega)} = {R_{ion} + \frac{1}{i\quad\omega\quad C_{ion}}}$which has the form of a series resistance-capacitance electricalequivalent circuit. Where ω is angular frequency defined as 2πf, where fis frequency, i=−1^(1/2), Z_(b)(ω) is the binding impedance, and R_(ion)and C_(ion) are equivalent binding resistance and capacitance of an ionbinding pathway. The value of the equivalent binding time constant,τ_(ion)=R_(ion)C_(ion), is related to a ion binding rate constant,k_(b), via τ_(ion)=R_(ion)C_(ion)=1/k_(b). Thus, the characteristic timeconstant of this pathway is determined by ion binding kinetics.

Induced E from a PEMF or PRF signal can cause current to flow into anion binding pathway and affect the number of Ca²⁺ ions bound per unittime. An electrical equivalent of this is a change in voltage across theequivalent binding capacitance C_(ion), which is a direct measure of thechange in electrical charge stored by C_(ion). Electrical charge isdirectly proportional to a surface concentration of Ca²⁺ ions in thebinding site, that is storage of charge is equivalent to storage of ionsor other charged species on cell surfaces and junctions. Electricalimpedance measurements, as well as direct kinetic analyses of bindingrate constants, provide values for time constants necessary forconfiguration of a PMF waveform to match a bandpass of target pathwaystructures. This allows for a required range of frequencies for anygiven induced E waveform for optimal coupling to target impedance, suchas bandpass.

Ion binding to regulatory molecules is a frequent EMF target, forexample Ca²⁺ binding to calmodulin (“CaM”). Use of this pathway is basedupon acceleration of wound repair, for example bone repair, thatinvolves modulation of growth factors released in various stages ofrepair. Growth factors such as platelet derived growth factor (“PDGF”),fibroblast growth factor (“FGF”), and epidermal growth factor (“EGF”)are all involved at an appropriate stage of healing. Angiogenesis andneovascularization are also integral to wound repair and can bemodulated by PMF. All of these factors are Ca/CaM-dependent.

Utilizing a Ca/CaM pathway a waveform can be configured for whichinduced power is sufficiently above background thermal noise power.Under correct physiological conditions, this waveform can have aphysiologically significant bioeffect.

Application of a Power SNR model to Ca/CaM requires knowledge ofelectrical equivalents of Ca²⁺ binding kinetics at CaM. Within firstorder binding kinetics, changes in concentration of bound Ca²⁺ at CaMbinding sites over time may be characterized in a frequency domain by anequivalent binding time constant, τ_(ion)=R_(ion)C_(ion), where R_(ion)and C_(ion) are equivalent binding resistance and capacitance of the ionbinding pathway. τ_(ion) is related to a ion binding rate constant,k_(b), via τ_(ion)=R_(ion)C_(ion)=1/k_(b). Published values for k_(b)can then be employed in a cell array model to evaluate SNR by comparingvoltage induced by a PRF signal to thermal fluctuations in voltage at aCaM binding site. Employing numerical values for PMF response, such asV_(max)=6.5×10⁻⁷ sec⁻¹, [Ca²⁺]=2.5 μM, K_(D)=30 μM,[Ca²⁺CaM]=K_(D)([Ca²⁺]+[CaM]), yields k_(b)=665 sec⁻¹ (τ_(ion)=1.5msec). Such a value for τ_(ion) can be employed in an electricalequivalent circuit for ion binding while power SNR analysis, can beperformed for any waveform structure.

According to an embodiment of the present invention a mathematical modelcan be configured to assimilate that thermal noise is present in allvoltage dependent processes and represents a minimum thresholdrequirement to establish adequate SNR. Power spectral density, S_(n)(ω),of thermal noise can be expressed as:S _(n)(ω)=4kT Re[Z _(M)(x,ω)]where Z_(M)(x,ω) is electrical impedance of a target pathway structure,x is a dimension of a target pathway structure and Re denotes a realpart of impedance of a target pathway structure. Z_(M)(x,ω) can beexpressed as:${Z_{M}( {x,\omega} )} = {\lbrack \frac{R_{e} + R_{i} + R_{g}}{\gamma} \rbrack{\tanh( {\gamma\quad x} )}}$

This equation clearly shows that electrical impedance of the targetpathway structure, and contributions from extracellular fluid resistance(“R_(e)”), intracellular fluid resistance (“R_(i)”) and intermembraneresistance (“R_(g)”) which are electrically connected to a targetpathway structure, all contribute to noise filtering.

A typical approach to evaluation of SNR uses a single value of a rootmean square (RMS) noise voltage. This is calculated by taking a squareroot of an integration of S_(n)(ω)=4kT Re[Z_(M)(x,ω)] over allfrequencies relevant to either complete membrane response, or tobandwidth of a target pathway structure. SNR can be expressed by aratio: ${SNR} = \frac{{V_{M}(\omega)}}{RMS}$where |V_(M)(ω)| is maximum amplitude of voltage at each frequency asdelivered by a chosen waveform to the target pathway structure.

An embodiment according to the present invention comprises a pulse burstenvelope having a high spectral density, so that the effect of therapyupon the relevant dielectric pathways, such as, cellular membranereceptors, ion binding to cellular enzymes and general transmembranepotential changes, is enhanced. Accordingly by increasing a number offrequency components transmitted to relevant cellular pathways, a largerange of biophysical phenomena, such as modulating growth factor andcytokine release and ion binding at regulatory molecules, applicable toknown healing mechanisms is accessible. According to an embodiment ofthe present invention applying a random, or other high spectral densityenvelope, to a pulse burst envelope of mono- or bi-polar rectangular orsinusoidal pulses inducing peak electric fields, between about 10⁻⁶andabout 100 V/cm, produces a greater effect on biological healingprocesses applicable to both soft and hard tissues.

According to yet another embodiment of the present invention by applyinga high spectral density voltage envelope as a modulating or pulse-burstdefining parameter, power requirements for such amplitude modulatedpulse bursts can be significantly lower than that of an unmodulatedpulse burst containing pulses within a similar frequency range. This isdue to a substantial reduction in duty cycle within repetitive bursttrains brought about by imposition of an irregular, and preferablyrandom, amplitude onto what would otherwise be a substantially uniformpulse burst envelope. Accordingly, the dual advantages, of enhancedtransmitted dosimetry to the relevant dielectric pathways and ofdecreased power requirement are achieved.

Referring to FIG. 1, wherein FIG. 1 is a flow diagram of a method fordelivering electromagnetic signals to angiogenesis andneovascularization target pathway structures such as ions and ligands ofplants, animals, and humans for therapeutic and prophylactic purposesaccording to an embodiment of the present invention. A mathematicalmodel having at least one waveform parameter is applied to configure atleast one waveform to be coupled to a angiogenesis andneovascularization target pathway structure such as ions and ligands(Step 101). The configured waveform satisfies a SNR or Power SNR modelso that for a given and known angiogenesis and neovascularization targetpathway structure it is possible to choose at least one waveformparameter so that a waveform is detectable in the angiogenesis andneovascularization target pathway structure above its backgroundactivity (Step 102) such as baseline thermal fluctuations in voltage andelectrical impedance at a target pathway structure that depend upon astate of a cell and tissue, that is whether the state is at least one ofresting, growing, replacing, and responding to injury. A preferredembodiment of a generated electromagnetic signal is comprised of a burstof arbitrary waveforms having at least one waveform parameter thatincludes a plurality of frequency components ranging from about 0.01 Hzto about 100 MHz wherein the plurality of frequency components satisfiesa Power SNR model (Step 102). A repetitive electromagnetic signal can begenerated for example inductively or capacitively, from said configuredat least one waveform (Step 103). The electromagnetic signal is coupledto a angiogenesis and neovascularization target pathway structure suchas ions and ligands by output of a coupling device such as an electrodeor an inductor, placed in close proximity to the target pathwaystructure (Step 104). The coupling enhances modulation of binding ofions and ligands to regulatory molecule in living tissues and cells.

FIG. 2 illustrates a preferred embodiment of an apparatus according tothe present invention. A miniature control circuit 201 is coupled to anend of at least one connector 202 such as wire. The opposite end of theat least one connector is coupled to a generating device such as a pairof electrical coils 203. The miniature control circuit 201 isconstructed in a manner that applies a mathematical model that is usedto configure waveforms. The configured waveforms have to satisfy a SNRor Power SNR model so that for a given and known angiogenesis andneovascularization target pathway structure, it is possible to choosewaveform parameters that satisfy SNR or Power SNR so that a waveform isdetectable in the angiogenesis and neovascularization target pathwaystructure above its background activity. A preferred embodimentaccording to the present invention applies a mathematical model toinduce a time-varying magnetic field and a time-varying electric fieldin a angiogenesis and neovascularization target pathway structure suchas ions and ligands comprising about 10 to about 100 msec bursts ofabout 1 to about 100 microsecond rectangular pulses repeating at about0.1 to about 10 pulses per second. Peak amplitude of the inducedelectric field is between about 1 uV/cm and about 100 mV/cm, variedaccording to a modified 1/f function where f=frequency. A waveformconfigured using a preferred embodiment according to the presentinvention may be applied to a angiogenesis, and neovascularizationtarget pathway structure such as ions and ligands for a preferred totalexposure time of under 1 minute to 240 minutes daily. However otherexposure times can be used. Waveforms configured by the miniaturecontrol circuit 201 are directed to a generating device 203 such aselectrical coils via connector 202. The generating device 203 delivers apulsing magnetic field configured according to a mathematical model,that can be used to provide treatment to a angiogenesis andneovascularization target pathway structure such as a heart in a chest204. The miniature control circuit applies a pulsing magnetic field fora prescribed title and can automatically repeat applying the pulsingmagnetic field for as many applications as are needed in a given timeperiod, for example 10 times a day. A preferred embodiment according tothe present invention can be positioned to treat the heart in a chest204 by a positioning device. Coupling a pulsing magnetic field to aangiogenesis and neovascularization target pathway structure such asions and ligands, therapeutically and prophylactically reducesinflammation thereby reducing pain and promotes healing. When electricalcoils are used as the generating device 203, the electrical coils can bepowered with a time varying magnetic field that induces a time varyingelectric field in a target pathway structure according to Faraday's law.An electromagnetic signal generated by the generating device 203 canalso be applied using electrochemical coupling, wherein electrodes arein direct contact with skin or another outer electrically conductiveboundary of a target pathway structure. Yet in another embodimentaccording to the present invention, the electromagnetic signal generatedby the generating device 203 can also be applied using electrostaticcoupling wherein an air gap exists between a generating device 203 suchas an electrode and a angiogenesis and neovascularization target pathwaystructure such as ions and ligands. An advantage of the preferredembodiment according to the present invention is that its ultralightweight coils and miniaturized circuitry allow for use with commonphysical therapy treatment modalities and at any body location for whichpain relief and healing is desired. An advantageous result ofapplication of the preferred embodiment according to the presentinvention is that a living organism's angiogenesis andneovascularization can be maintained and enhanced.

FIG. 3 depicts a block diagram of a preferred embodiment according tothe present invention of a miniature control circuit 300. The miniaturecontrol circuit 300 produces waveforms that drive a generating devicesuch as wire coils described above in FIG. 2. The miniature controlcircuit can be activated by any activation means such as an on/offswitch. The miniature control circuit 300 has a power source such as alithium an output voltage of 3.3 V but other voltages can be used. Inanother embodiment according to the present invention the power sourcecan be an external power source such as an electric current outlet suchas an AC/DC outlet, coupled to the present invention for example by aplug and wire. A switching power supply 302 controls voltage to amicro-controller 303. A preferred embodiment of the micro-controller 303uses an 8 bit 4 MHz micro-controller 303 but other bit MHz combinationmicro-controllers may be used. The switching power supply 302 alsodelivers current to storage capacitors 304. A preferred embodiment ofthe present invention uses storage capacitors having a 220 uF output butother outputs can be used. The storage capacitors 304 allow highfrequency pulses to be delivered to a coupling device such as inductors(Not Shown). The micro-controller 303 also controls a pulse shaper 305and a pulse phase timing control 306. The pulse shaper 305 and pulsephase timing control 306 determine pulse shape, burst width, burstenvelope shape, and burst repetition rate. An integral waveformgenerator, such as a sine wave or arbitrary number generator can also beincorporated to provide specific waveforms. A voltage level conversionsub-circuit 308 controls an induced field delivered to a target pathwaystructure. A switching Hexfet 308 allows pulses of randomized amptitudeto be delivered to output 309 that routes a waveform to at least onecoupling device such as an inductor. The micro-controller 303 can alsocontrol pathway structure such as a molecule, cell, tissue, and organ.The miniature control circuit 300 can be constructed to apply a pulsingmagnetic field for a prescribed time and to automatically repeatapplying the pulsing magnetic field for as many applications as areneeded in a given time period, for example 10 times a day. A preferredembodiment according to the present invention uses treatments times ofabout 10 minutes to about 30 minutes.

Referring to FIG. 4 an embodiment according to the present invention ofa waveform 400 is illustrated. A pulse 401 is repeated within a burst402 that has a finite duration 403. The duration 403 is such that a dutycycle which can be defined, as a ratio of burst duration to signalperiod is between about 1 to about 10⁻⁵. A preferred embodimentaccording to the present invention utilizes pseudo rectangular 10microsecond pulses for pulse 401 applied in a burst 402 for about 10 toabout 50 msec having a modified 1/f amplitude envelope 404 and with afinite duration 403 corresponding to a burst period of between about 0.1and about 10 seconds.

EXAMPLE 1

The Power SNR approach for PMF signal configuration has been testedexperimentally on calcium dependent myosin phosphorylation in a standardenzyme assay. The cell-free reaction mixture was chosen forphosphorylation rate to be linear in time for several minutes, and forsub-saturation Ca²⁺ concentration. This opens the biological window forCa²⁺/CaM to be EMF-sensitive. This system is not responsive to PMF atlevels utilized in this study if Ca²⁺ is at saturation levels withrespect to CaM, and reaction is not slowed to a minute time range.Experiments were performed using myosin light chain (“MLC”) and myosinlight chain kinase, (“MLCK”) isolated from turkey gizzard. A reactionmixture consisted of a basic solution containing 40 mM Hepes buffer, pH7.0; 0.5 mM magnesium acetate; 1 mg/ml bovine serum albumin, 0.1% (w/v)Tween 80; and 1 mM EGTA12. Free Ca²⁺ was varied in the 1-7 μM range.Once Ca²⁺ buffering was established, freshly prepared 70 nM CaM, 160 nMMLC and 2 nM MLCK were added to the basic solution to form a finalreaction mixture. The low MLC/MLCK ratio allowed linear time behavior inthe minute time range. This provided reproducible enzyme activities andminimized pipetting time errors.

The reaction mixture, was freshly prepared daily for each series ofexperiments and was aliquoted in 100 μL portions, into 1.5 ml Eppendorftubes. All Eppendorf tubes, containing reaction mixture were kept at 0°C. then transferred to a specially designied water bath maintained at37±0.1° C. by constant perfusion of water prewarmed by passage through aFisher Scientific model 900 heat exchanger. Temperature was monitoredwith a thermistor probe such as a Cole-Parmer model 8110-20, immersed inone Eppendorf tube during all experiments. Reaction was initiated with2.5 μM 3.2P ATP, and was stopped with Laemmli Sample Buffer solutioncontaining 30 μM EDTA. A minimum of five blank samples were counted ineach experiment. Blanks comprised a total assay mixture minus one of theactive components Ca²⁺, CaM, MLC or MLCK. Experiments for which blankcounts were higher than 300 cpm were rejected. Phosphorylation wasallowed to proceed for 5 min and was, evaluated by counting 32Pincorporated in MLC using a TM Analytic model 5303 Mark V liquidscintillation counter.

The signal comprised repetitive bursts of a high frequency waveform.Amplitude was maintained constant at 0.2 G and repetition rate was 1burst/sec for all exposures. Burst duration varied from 65 μsec to 1000μsec based upon projections of Power SNR analysis which showed thatoptimal Power SNR would be achieved as burst duration approached 500μsec. The results are shown in FIG. 7 wherein burst width 701 in μsec isplotted on the x-axis and Myosin Phosphorylation 702 as treated/sham isplotted on the y-axis. It can be seen that the PMF effect on Ca²⁺binding to CaM approaches its maximum at approximately 500 μsec, just asillustrated by the Power SNR model.

These results confirm that a PMF signal, configured according to anembodiment of the present invention, would maximally increase myosinphosphorylation for burst durations sufficient to achieve optimal PowerSNR for a given magnetic field amplitude.

EXAMPLE 2

According to an embodiment of the present, invention use of a Power SNRmodel was further verified in an in vivo wound repair model. A rat woundmodel has been well characterized both biomechanically andbiochemically, and was used in this study. Healthy, young adult maleSprague Dawley rats weighing more than 300 grams were utilized.

The animals were anesthetized with an intraperitoneal dose of Ketamine75 mg/kg and Medetomidine 0.5 mg/kg. After adequate anesthesia had beenachieved, the dorsum was shaved, prepped with a dilute betadine/alcoholsolution, and draped using sterile technique. Using a #10 scalpel, an8-cm linear incision was performed through the skin down to the fasciaon the dorsum of each rat. The wound edges were bluntly dissected tobreak any remaining dermal fibers, leaving an open wound approximately 4cm in diameter. Hemostasis was obtained with applied pressure to avoidany damage to the skin edges. The skin edges were then closed with a 4-0Ethilon running suture. Post-operatively, the animals receivedBuprenorphine 0.1-0.5 mg/kg, intraperitoneal. They were placed inindividual cages and received food and water ad libitum.

PMF exposure comprised two pulsed radio frequency waveforms. The firstwas a standard clinical PRF signal comprising a 65 μsec burst of 27.12MHz sinusoidal waves at 1 Gauss, amplitude and repeating at 600bursts/sec. The second was a PRF signal reconfigured according to anembodiment of the present invention. For this signal burst duration wasincreased to 2000 μsec and the amplitude and repetition rate werereduced to 0.2 G and 5 bursts/sec respectively. PRF was applied for 30minutes twice daily.

Tensile strength was performed immediately after wound excision. Two 1cm width strips of skin were transected perpendicular to the scar fromeach sample and used to measure the tensile strength in kg/mm². Thestrips were excised from the same area in each rat to assure consistencyof measurement. The strips were then mounted on a maximum forcegenerated before the wound pulled apart was recorded. The final tensilestrength for comparison was determined by taking the average of themaximum load in kilograms per mm² of the two strips from the same wound.

The results showed average tensile strength for the 65 μsec 1 Gauss PRFsignal was 19.3±4.3 kg/mm² for the exposed group versus 13.0±3.5 kg/mm²for the control group (p<0.01), which is a 48% increase. In contrast,the average tensile strength for the 2000 μsec 0.2 Gauss PRF signal,configured according to an embodiment of the present invention using aPower SNR model was 21.2±5.6 kg/mm² for the treated group versus13.7±4.1 kg/mm² (p<0.01) for the control group, which is a 54% increase.The results for the two signals were not significantly different fromeach other.

These results demonstrate that an embodiment of the present inventionallowed a new PRF signal to be configured that could be produced withsignificantly lower power. The PRF signal configured according to anembodiment of the present invention, accelerated would repair in the ratmodel in a low power manner versus that for a clinical PRF signal whichaccelerated wound repair but required more than two orders of magnitudemore power to produce.

EXAMPLE 3

In this example Jurkat cells react to PMF stimulation of a T-cellreceptor with cell cycle arrest and thus behave like normalT-lymphocytes stimulated by antigens at the T-cell receptor such asanti-CD3. For example in bone healing, results have shown both 60 Hz andPEMF fields decrease DNA synthesis of Jurkat cells, as is expected sincePMF interacts with the T-cell receptor in the absence of a costimulatorysignal. This is consistent with an anti-inflammatory response, as hasbeen observed in clinical applications of PMF stimuli. The PEMF signalis more effective. A dosimetry analysis performed according to anembodiment of the present invention demonstrates why both signals areeffective and why PEMF signals have a greater effect than 60 Hz signalson Jurkat cells in the most EMF-sensitive growth stage.

Comparison of dosimetry from the two signals employed involvesevaluation of the ratio of the Power spectrum of the thermal noisevoltage that is Power SNR, to that of the induced voltage at theEMF-sensitive target pathway structure. The target pathway structureused is ion binding at receptor sites on Jurkat cells suspended in 2 mmof culture medium. The average peak electric field at the binding sitefrom a PEMF signal comprising 5 msec burst of 200 μsec pulses repeatingat 15/sec, was 1 mV/cm, while for a 60 Hz signal it was 50 μV/cm.

EXAMPLE 4

In this example electromagnetic field energy was used to stimulateneovascularization in an in vivo model. Two different signal wereemployed, one configured according to prior art and a second configuredaccording to an embodiment of the present invention.

One hundred and eight Sprague-Dawley male rats weighing approximately300 grams each, were equally divided into nine groups. All animals wereanesthetized with a mixture of ketamine/acepromazine/Stadol at 0.1 cc/g.Using sterile surgical techniques, each animal had a 12 cm to 14 cmsegment of tail artery harvested using microsurgical tehnique. Theartery was flushed with 60 U/ml of heparinized saline to remove anyblood or emboli. These tail vessels, with an average diameter of 0.4 mmto 0.5 mm, were then sutured to the transected proximal and distalsegments of the right femoral artery using two end-to-end anastomoses,creating a femoral arterial loop. The resulting loop was then placed ina subcutaneous pocket created over the animal's abdominal wall/groinmusculature, and the groin incision was closed with 4-0 Ethilon. Eachanimal was then randomly placed into one of nine groups: groups 1 to 3(controls), these rats received no electromagnetic field treatments andwere killed at 4, 8, and 12 weeks; groups 4 to 6, 30 min. treatmentstwice a day to using 0.1 gauss electromagnetic fields for 4, 8, and 12weeks (animals were killed at 4, 8, and 12 weeks, respectively); andgroups 7 to 9, 30 min. treatments twice a day using 2.0 gausselectromagnetic fields for 4, 8, and 12 weeks (animals were killed at 4,8, and 12 weeks, respectively).

Pulsed electromagnetic energy was as applied to the treated groups usinga device constructed according to an embodiment of the presentinvention. Animals in the experimental groups were treated for 30minutes twice a day at either 0.1 gauss or 2.0 gauss, using short pulses(2 msec to 20 msec) 27.12 MHz. Animals were positioned on top of theapplicator head and confined to ensure that treatment was properlyapplied. The rats were reanesthetized with ketamine/acepromazine/Stadolintraperitoneally and 100 U/kg of heparin intravenously. Using theprevious groin incision the femoral artery was identified and checkedfor patency. The femoral/tail artery loop was then isolated proximallyand distally from the anastomoses sites, and the vessel was clamped off.Animals were then killed. The loop was injected with saline followed by0.5 cc to 1.0 cc of colored latex through a 25-gauge, cannula andclamped. The overlying abdominal skin was carefully resected, and thearterial loop was exposed. Neovascularization was quantified bymeasuring the surface area covered by new blood-vessel formationdelineated by the intraluminal latex. All results were analyzed usingthe SPSS statistical analysis package.

The most noticeable difference in neovascularization between treatedversus untreated rats occurred at week 4. At that time, no new vesselformation was found among controls, however, each of the treated groupshad similar statistically significant evidence of neovascularization at0 cm2 versus 1.42±0.80 cm2 (p<0.001). These areas appeared as a latexblush segmentally distributed along the sides of the arterial loop. At 8weeks, controls began to demonstrate neovascularization measured at0.7±0.82 cm2. Both treated groups at 8 weeks again had approximatelyequal statistically significant (p<0.001) outcroppings of blood vesselsof 3.57±1.82 cm2 for the 0.1 gauss group and of 3.77±1.82 cm2 for the2.0 gauss group. At 12 weeks, animals in the control group displayed1.75±0.95 cm2 of neovascularization, whereas the 0.1 gauss groupdemonstrated 5.95±3.25 cm2, and the 2.0 gauss group showed 6.20±3.95 cm2of arborizing vessels. Again, both treated groups displayed comparablestatistically significant findings (p<0.001) over controls.

These experimental findings demonstrate that electromagnetic fieldstimulation of an isolated arterial loop according to an embodiment ofthe present invention increases the amount of quantifiableneovascularization in an in vivo rat model. Increased angiogenesis wasdemonstrated in each of the treated groups at each of the sacrificedates. No differences were found between the results of the two gausslevels tested as predicted by the teachings of the present invention.

Having described embodiments, for an apparatus and a method fordelivering electromagnetic treatment to human, animal and plantmolecules, cells, tissue and organs, it is noted that modifications andvariations can be made by person skilled in the art in light of theabove teachings. It is therefore to be understood that changes may bemade in the particular embodiments of the invention disclosed which arewithin the scope and spirit of the invention as defined by the appendedclaims.

1) A method for electromagnetic treatment of living tissues and cells byenhancing angiogenesis and neovascularization comprising the steps of:Configuring at least one waveform according to a mathematical modelhaving at least one waveform parameter, said at least one waveform to becoupled to a angiogenesis and neovascularization target pathwaystructure; Choosing a value of said at least one waveform parameter sothat said at least waveform is configured to be detectable in saidangiogenesis and neovascularization target pathway structure abovebackground activity in said angiogenesis and neovascularization targetpathway is structure; Generating an electromagnetic signal from saidconfigured at least one waveform; and Coupling said electromagneticsignal to said angiogenesis and neovascularization target pathwaystructure using a coupling device. 2) The method of claim 1, whereinsaid at least one waveform parameter includes at least one of afrequency component parameter that configures said at least one waveformto repeat between about 0.01 Hz and about 100 MHz, a burst amplitudeenvelope parameter that follows a mathematically defined amplitudefunction, a burst width parameter that varies at each repetitionaccording to a mathematically defined width function, a peak inducedelectric field parameter varying between about 1 μV/cm and about 100mV/cm in said target pathway structure according to a mathematicallydefined function, and a peak induced magnetic electric field parametervarying between about 1 μT and about 0.1 T in said target pathwaystructure according to a mathematically defined function. 3) The methodof claim 1, wherein said angiogenesis and neovascularization targetpathway structure includes at least one of ions and ligands. 4) Themethod of claim 1, further comprising the step of binding ions andligands to regulatory molecules in living cells and tissues therebymodulating angiogenesis and neovascularization. 5) The method of claim4, wherein said binding of ions and ligands includes modulating Calciumto Calmodulin binding. 6) The method of claim 4, wherein said binding ofions and ligands includes modulating growth factor production in livingcells and tissues. 7) The method of claim 4, wherein said binding ofions and ligands, includes modulating cytokine production in livingcells and tissues. 8) The method of claim 4, wherein said binding ofions and ligands includes modulating growth factors and cytokinesrelevant to angiogenesis and neovascularization. 9) The method of claim4, wherein said binding of ions and ligands includes modulatingangiogenesis and neovascularization for treatment of bone fractures anddisorders. 10) The method of claim 4, wherein said binding of ions andligands includes modulating angiogenesis and neovascularization fortreatment of cardiovascular diseases. 11) The method of claim 4, whereinsaid binding of ions and ligands includes modulating angiogenesis andneovascularization for treatment of cerebral diseases. 12) The method ofclaim 4, wherein said binding of ions and ligands includes modulatingangiogenesis and neovascularization for treatment of cerebrovasculardisease. 13) The method of claim 4, wherein said binding of ions andligands includes modulating angiogenesis and neovascularization fortreatment peripheral vascular disease. 14) The method of claim 4,wherein said binding of ions and ligands includes modulatingangiogenesis and neovascularization for treatment of diseased orischemic cells and tissues. 15) The method of claim 4, wherein saidbinding of ions and ligands includes modulating angiogenesis andneovascularization for treatment of an acute or chronic soft tissuewound. 16) The method of claim 4, wherein said binding of ions andligands includes modulating angiogenesis and neovascularization fortreatment of sprains strains and contusions. 17) An electromagnetictreatment apparatus for plants, animals, and humans to enhanceangiogenesis and neovascularization comprising: A waveform configurationmeans for configuring at least one waveform to be coupled to aangiogenesis and neovascularization target pathway structure accordingto a mathematical model having at least one waveform parameter capableof being chosen so that said at least one waveform is configured to bedetectable in said angiogenesis and neovascularization target structureabove background activity in said angiogenesis and neovascularizationtarget pathway structure; An electromagnetic signal generating meansconnected to said waveform device by at least one connecting means forgenerating an electromagnetic signal from said configured at least onewaveform; and A coupling device connected by at least one connectingmeans to said electromagnetic signal generating device for coupling saidelectromagnetic signal to said angiogenesis and neovascularizationtarget pathway structure. 18) The electromagnetic treatment apparatus ofclaim 17, wherein said at least one waveform parameter includes at leastone of a frequency component parameter that configures said at least onewaveform to repeat between about 0.01 Hz an about 100 MHz according to amathematical function, a burst amplitude envelope parameter that followsa mathematically defined amplitude function, a burst width parameterthat varies at each repetition according to a mathematically definedwidth function, a peak induced electric field parameter varying betweenabout 1 μV/cm and about 100 mV/cm in said angiogenesis andneovascularization target pathway structure according to amathematically defined function, and a peak induced magnetic electricfield parameter varying between about 1 μT and about 0.1 T in saidangiogenesis and neovascularization target pathway structure accordingto a mathematically defined function. 19) The electromagnetic signalgenerating means of claim 17 wherein the signal is inductively coupledto living cells and tissues wherein Calcium binding to Calmodulin ismodulated. 20 ) The electromagnetic signal generating means of claim 17wherein the signal is capacitively coupled to living cells and tissueswherein Calcium binding to Calmodulin is modulated. 21) Theelectromagnetic signal generating means of claim 17 wherein the signalis inductively coupled to living cells and tissues wherein growthfactors and cytokines relevant to angiogenesis and neovascularizationare modulated. 22) The electromagnetic signal generating means of claim21 wherein the growth factors include at least one of fibroblast growthfactors, platelet derived growth factors and interleukin growth factors.23) The electromagnetic signal generating means of claim 17 wherein thesignal is capacitively coupled to living cells and tissues whereingrowth factors and cytokines relevant to angiogenesis andneovascularization are modulated. 24) The electromagnetic signalgenerating means of claim 23 wherein the growth factors include at leastone of fibroblast growth factors, platelet derived growth factors andinterleukin growth factors. 25) The electromagnetic signal generatingmeans of claim 17 wherein the signal is inductively coupled to livingcells and tissues to modulate growth factor production. 26) Theelectromagnetic signal generating means of claim 17 wherein the signalis capacitively coupled to living cells and tissues to modulate growthfactor production. 27) The electromagnetic signal generating means ofclaim 17 wherein the signal is inductively coupled to living cells andtissues to modulate cytokine production. 28) The electromagnetic signalgenerating means of claim 17 wherein the signal is capacitively coupledto living cells and tissues to modulate cytokine production. 29) Theelectromagnetic signal generating means of claim 17 wherein the signalis inductively coupled to living cells and tissues to modulateangiogenesis and neovascularization for the treatment of bone fracturesand disorders. 30) The electromagnetic signal generating means of claim17 wherein the signal is capacitively coupled to living cells andtissues to modulate angiogenesis and neovascularization for thetreatment of bone fractures and disorders. 31) The electromagneticsignal generating means of claim 17 wherein the signal is inductivelycoupled to living cells and tissues to modulate angiogenesis andneovascularization for the treatment of cardiovascular diseases. 32) Theelectromagnetic signal generating means of claim 17 wherein the signalis capacitively coupled to living cells and tissues to modulateangiogenesis and neovascularization for the treatment of cardiovasculardiseases. 33) The electromagnetic signal generating means of claim 17wherein the signal is inductively coupled to living cells and tissues tomodulate angiogenesis and neovascularization for the treatment ofcerebral diseases. 34) The electromagnetic signal generating means ofclaim 17 wherein the signal is capacitively coupled to living cells andtissues to modulate angiogenesis and neovascularization for thetreatment of cerebral diseases. 35) The electromagnetic signalgenerating means of claim 17 wherein the signal is inductively coupledto living cells and tissues to modulate angiogenesis andneovascularization for the treatment of cerebrovascular disease. 36) Theelectromagnetic signal generating means of claim 17 wherein the signalis capacitively coupled to living cells and tissues to modulateangiogenesis and neovascularization for the treatment of cerebrovasculardisease. 37) The electromagnetic signal generating means of claim 17wherein the signal is inductively coupled to living cells and tissues tomodulate angiogenesis and neovascularization for the treatment ofperipheral vascular disease. 38) The electromagnetic signal generatingmeans of claim 17 wherein the signal is capacitively coupled to livingcells and tissues to modulate angiogenesis and neovascularization forthe treatment of peripheral vascular disease. 39) The electromagneticsignal generating means of claim 17 wherein the signal is inductivelycoupled to living cells and tissues to modulate angiogenesis andneovascularization for the treatment of diseased or ischemic cells andtissues. 40) The electromagnetic signal generating means of claim 17wherein the signal is capacitively coupled to living cells and tissuesto modulate angiogenesis and neovascularization for the treatment ofdiseased or ischemic cells and tissues. 41) The electromagnetic signalgenerating means of claim 17 wherein the signal is inductively coupledto living cells and tissues to modulate angiogenesis andneovascularization for the treatment of an acute or chronic soft tissuewound. 42) The electromagnetic signal generating means of claim 17wherein the signal is capacitively coupled to living cells and tissuesto modulate angiogenesis and neovascularization for the treatment of anacute or chronic soft tissue wound. 43) The electromagnetic signalgenerating means of claim 17 wherein the signal is inductively coupledto living cells and tissues to modulate angiogenesis andneovascularization for the treatment of sprains strains and contusions.44) The electromagnetic signal generating means of claim 17 wherein thesignal is capacitively coupled to living cells and tissues to modulateangiogenesis and neovascularization for the treatment of sprains strainsand contusions.